Review
Effects of probiotic supplementation during
pregnancy on metabolic outcomes: A systematic
review and meta-analysis of randomized controlled
trials
Maria Masulli
a,*, Ester Vitacolonna
b, Federica Fraticelli
b, Giuseppe Della Pepa
a,
Edoardo Mannucci
c, Matteo Monami
caDepartment of Clinical Medicine and Surgery, ‘‘Federico II” University of Naples, Italy
bDepartment of Medicine and Aging, School of Medicine and Health Sciences, ‘‘G. d’Annunzio” University, Chieti, Pescara, Italy cDiabetology, Careggi Hospital and University of Florence, Italy
A R T I C L E I N F O Article history:
Received 27 December 2019 Received in revised form 13 February 2020 Accepted 2 March 2020 Available online 16 March 2020
Keywords: Probiotics Gestational diabetes Glycemic control Maternal outcomes Fetal outcomes A B S T R A C T
Aim: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of probiotics in pregnancy on the incidence of gestational dia-betes (GDM) and fasting plasma glucose (FPG).
Methods: A MEDLINE, EMBASE, Scopus and Cochrane search (up to May 30th, 2019) was per-formed to identify RCTs of comparison of probiotics with placebo/active comparators in pregnant women. Principal endpoints were the incidence of GDM and the change of FPG. Other maternal and fetal outcomes were secondary endpoints. Mantel-Haenszel Odds Ratio with 95% CI (MH-OR) was calculated for dichotomous outcomes, whereas standard-ized differences in means was calculated for continuous variables. (PROSPERO registration CRD42019139889).
Findings: A total of 17 RCTs, all versus placebo, was identified. The overall quality of the tri-als was satisfactory. No effect of probiotics on incidence of GDM (MH-OR: 0.77[0.51,1.16], p = 0.21,I2:62%) was observed, with a small but significant reduction of FPG (mean differ-ence 1.01 [ 1.96, 0.06]mg/dl, p = 0.02, I2:46%). Among secondary endpoints, a significant reduction of maternal insulin (both in women with or without diabetes) was observed in the probiotics group.
Interpretation: Probiotics during pregnancy do not reduce the incidence of GDM, with a very little (statistically but not clinically significant) reduction of fasting plasma glucose.
Ó 2020 Published by Elsevier B.V.
https://doi.org/10.1016/j.diabres.2020.108111 0168-8227/Ó 2020 Published by Elsevier B.V.
* Corresponding author at: Department of Clinical Medicine and Surgery, ‘‘Federico II” University of Naples, via S. Pansini 5, 80131 Naples, Italy.
E-mail address:maria.masulli@unina.it(M. Masulli).
Contents available atScienceDirect
Diabetes Research
and Clinical Practice
jo u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m /l o c a t e / di a br e sContents
1. Introduction . . . 2
2. Methods . . . 2
2.1. Search strategy and selection criteria . . . 2
2.2. Data analysis . . . 3 2.3. Statistical analyses . . . 3 3. Results . . . 3 3.1. Trials characteristics . . . 3 3.2. Primary outcomes . . . 3 3.3. Secondary outcomes . . . 4 3.3.1. Mother . . . 4 3.3.2. Infant. . . 7 4. Discussion . . . 7
5. Role of the funding source. . . 8
Author contributions . . . 8
Declaration of Competing Interest. . . 8
Appendix A. Supplementary material . . . 8
References . . . 8
1.
Introduction
Gestational diabetes mellitus (GDM) is a condition of glucose tolerance that is first recognized during pregnancy and that can be associated with an increased risk of several maternal and fetal complications[1]. During pregnancy, some changes occur in the gut microbiome. Some studies link maternal microbial dysbiosis to increased insulin resistance, as well as inflammatory state and oxidative stress[2]. Probiotics are living and viable micro-organisms capable of providing, when ingested in adequate quantities, specific benefits to the health of their host. Probiotic supplementation during pregnancy seems to have some benefits on metabolic health: results of some randomized controlled trials (RCTs) suggest that probi-otics reduce the incidence of GDM[3,4] and reduce fasting plasma glucose (FPG) and markers of insulin resistance[5,6]; on the contrary, other RCTs showed that probiotics had no influence on the prevention of GDM[7], nor on FPG and fast-ing serum insulin[8–9].
The inconsistency of results could be due to several reasons: generally, trials have small sample size; they often compare treatment arms (probiotics vs placebo) in addition to con-founding molecules (i.e., inulin) making the interpretation of the independent effect of probiotics problematic[10]; further-more, the probiotics used in experimental arms vary widely among studies. The limitation of the sample size could be over-come by combining studies in meta-analyses, thus increasing statistical power and producing more reliable estimates of the effect size. Unfortunately, results of meta-analyses are also inconsistent, mainly due to heterogeneity of RCTs included. In fact, the effects of probiotics on glycemic control in GDM are reported to be either neutral[11]or beneficial[12]. A previous meta-analysis performed to evaluate the effect of probiotics in pregnancy on the risk of GDM[12]reported a significant reduction of the endpoint in the group treated with probiotics as compared with placebo: however, this meta-analysis included only 3 trials with limited sample size.
More recently, larger RCTs have been published[13–17]. The SPRING study [13] has shown that probiotics
supplementation throughout pregnancy from the first half of the second trimester does not reduce the incidence of GDM in overweight and obese women. Another trial con-ducted in 439 overweight and obese women[15]has shown no benefits of probiotic supplementation neither on the inci-dence of GDM nor on glucose metabolism, nor on maternal and neonatal outcomes.
Based on the inconsistency of previous results and in con-sideration of the publication of recent larger trials, we per-formed a systematic review and meta-analysis of RCTs aimed to evaluate the health effects of probiotic supplemen-tation in pregnant women with or without diabetes. In women without diabetes, the principal outcome was the inci-dence of GDM; in women with GDM, the principal outcome was the effect on FPG. We also explored the effects of probi-otics supplementation on maternal outcomes, other than metabolic, and fetal outcomes.
2.
Methods
The present meta-analysis of RCTs has been registered on PROSPERO website (PROSPERO CRD42019139889;https://www. crd.york.ac.uk/prospero/#recordDetails). This meta-analysis is reported following the criteria of PRISMA statement[18].
2.1. Search strategy and selection criteria
A MEDLINE (https://www.ncbi.nlm.nih.gov/PubMed), EMBASE (https://www.embase.com/) SCOPUS (https://www.
scopus.com/), and Cochrane database (https://
www.cochranelibrary.com/) search was performed to iden-tify all clinical RCTs (with no language restriction), enrolling women in pregnancy with and without diabetes, up to May 30th, 2019 in which oral supplementation with probiotics has been compared either with placebo or active compara-tors. In addition, we used supplementary approaches to identify further studies (grey literature), such as hand
searching of journals, checking reference lists, and searching regulatory agency websites (Food and Drugs Administration and European Medicine Agency databases). Completed but yet unpublished trials were searched in the www.clinicaltrials.gov register. Detailed information on search string is reported in Supplementary materials (Table S1). The identification of relevant abstracts, the selec-tion of studies, and extracselec-tion were performed indepen-dently by two of the authors (M.M. and M.M.), and conflicts resolved by a third investigator (E.V.).
For elaboration of the analysis question, the PICOS method was used: participants (pregnant women), interventions (oral probiotics supplementation), comparison (placebo or active comparison), outcomes (incidence of GDM in women without diabetes and FPG in women with or without diabetes), study design (meta-analysis of RCTs).
We included studies which met the following inclusion/ex-clusion criteria: (1) RCTs comparing any type of probiotic with placebo or active comparator; (2) that included pregnant women at any age and any stage of pregnancy; (3) that included women without diabetes or women with gestational diabetes; (4) evaluating any probiotic supplementation, irre-spective of the dose or composition (single or multiple strains); (5) administered orally; (6) articles reporting results on the incidence of GDM, or change of FPG, insulin, home-ostasis model assessment of insulin resistance (HOMA), or maternal and fetal outcomes. We excluded: (1) articles other than RCTs; (2) trials using administration route other than oral; (3) trials that compare probiotics + add-on therapy vs placebo/active comparator that not included the add-on ther-apy (vitamin supplementation was allowed, if it was given to both treatment arms).
2.2. Data analysis
For all published trials, results reported in published papers were used as the primary source of information, whereas results of unpublished trials were retrieved, if available, on www.clinicaltrials.gov. Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) was used for the assess-ment of the risk of bias. RoB 2 is structured into a fixed set of domains of bias, focusing on different aspects of trial design, conduct, and reporting. A proposed judgment about the risk of bias arising from each domain is generated by an algorithm. Judgment can be ’Low’ or ’High’ risk of bias or can express ’Some concerns’. The risk of bias for each study included in the present meta-analysis was reviewed indepen-dently by two of the authors (M.M. and M.M.), and conflicts resolved by a third investigator (E.V.) The following parameters/information were extracted: first author, year of publication, name of the investigational drug, form, and dosage, study design, comparator, add-on therapy, beginning of treatment and duration of treatment, number of patients in each arm, mean age, and mean prepregnancy or early pregnancy Body Mass Index (BMI).
The principal endpoints were: the incidence of GDM (diag-nosed with oral glucose tolerance test at the 24-28th gesta-tional week) in trials performed in women without diabetes and the FPG at the end of treatment in trials enrolling women with and without diabetes.
Secondary endpoints were:
(a) Mother: serum fasting insulin, HOMA index, body weight at the end of treatment, and preeclampsia and caesarean section at the end of pregnancy.
(b) Infant: macrosomia, birth weight, preterm, jaundice, neonatal hypoglycemia, Intensive Care Unit (ICU) admission; intrauterine/perinatal death.
2.3. Statistical analyses
Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95%, CI) and between-group difference-in means (mean difference: MD) with 95%, CI were calculated, on an intention-to-treat basis, for dichotomic and continuous out-comes, respectively. Heterogeneity was assessed using I2 statistics. Even when low heterogeneity was detected, a random-effects model was applied as the primary analysis, because the validity of tests of heterogeneity can be limited with a small number of events in each component study. Fixed effect models were applied for sensitivity analysis.
All analyses were performed using Review Manager 5.3.5; Copenhagen: The Nordic Cochrane Centre, The Cochrane Col-laboration, 2014.
3.
Results
3.1. Trials characteristics
Fig. 1reports the trial flow summary. The diagram follows the recommendations of PRISMA statement. A total of 17 trials (Tables 1 and 2), all versus placebo, fulfilling the inclusion cri-teria was identified; out of 11 trials performed in women without diabetes, only 7 reported information on incident dia-betes (Table 1). All these studies reported at least one event [4,6,7,13–15,17]. A total of 6 studies enrolling women with GDM [5,8,16,19–21] and 9 studies enrolling women without GDM were included in the analysis for FPG (Table 2) [4,6,7,9,13–15,17,22]. Only 2 studies, performed in women without diabetes, did not report information on FPG but were included in the analysis for other endpoints (Table 2)[23,24]. The overall quality of trials was satisfactory for most of the items of the Rob 2 tool, apart from ‘‘other bias” (i.e. funding from industries”) that was ‘‘unclear” for several trials (Fig. S1ofSupplementary Material).
The median duration of treatment with probiotics was 11.5 weeks. The mean age and BMI of the included studies were 29.4 years and 28.5 Kg/m2, respectively (Tables 1 and 2).
3.2. Primary outcomes
Trials on women without diabetes reported 177 and 200 cases of incident GDM in probiotics and control group, respectively, showing no effect of probiotics on the incidence of diabetes (MH-OR: 0.77 [0.51, 1.16], p = 0.21, I2: 62%; Fig. 2). Similar results were obtained in a sensitivity analysis using a fixed-effect model (0.85 [0.68, 1.07], p = 0.17) (data not shown).
Information on fasting plasma glycemia at the end of treatment was reported in 15 trials (Fig. 3). Probiotics appears to produce a small but significant reduction of FPG in compar-ison with placebo (MD: 1.05 [ 1.95, 0.16] mg/dl; p = 0.02, I2:45%;Fig. 3). When considering separately trials enrolling women with and without diabetes, this effect did not reach the statistical significance in either group, and the difference between subgroups of trials was not statistically significant (Fig. 3). A separate analysis considering the type of probiotic scheme used revealed no significant differences (Fig. S2). In sensitivity analyses, this result did not maintain the statisti-cal significance when using a fixed-effect model (MD, 95% CI: 0.33 [ 1.09, 0.43]; p = 0.39) or excluding trials with a risk of bias uncertain or high[7,19,22](MD, 95% CI: 0.31 [ 1.14, 0.52]; p = 0.46).
3.3. Secondary outcomes
3.3.1. Mother
When analysing the effect of probiotics on fasting serum insu-lin in trials reporting this information (8 trials), a significant
reduction was observed in comparison with placebo (MD, 95% CI: 1.63 [-2.56, 0.71]lU/ml, p < 0.001,Fig. S3), to a sim-ilar extent both in women with diabetes (n = 3 trials, MD, 95% CI: 1.83 [ 4.22, 0.55]lU/ml, p = 0.13) and in women without diabetes (n = 5, MD, 95% CI: 1.74[ 2.82, 0.67] lU/ml, p = 0.002). Similar results, although not reaching full statistical significance, were obtained for HOMA index (MD, 95% CI: 0.19 [ 0.44, 0.05], p = 0.12, Fig. S4), with no difference between trials enrolling women with or without diabetes (data not shown). No significant difference in maternal body weight at the end of the treatment period was detected (MD, 95%CI:
1.61 [-3.83, 0.61] kg, p = 0.16,Fig. S5).
Information on preeclampsia was reported in 8 trials, with no effect of probiotics treatment in comparison with placebo (MH-OR, 95%, CI: 1.42 [0.92, 2.20], p = 0.12, Fig. S6). Similar results were obtained when separately analyzing trials in women with or without diabetes (data not shown). Caesarean section did not significantly differ between the two groups (MH-OR, 95%, CI: 0.96 [0.79, 1.16], p = 0.65,Fig. S7), with no dif-ferences when considering separately trials enrolling women with or without diabetes.
Fig. 1 – PRISMA 2009 Flow Diagram.
publication year (ref) (CFU per capsule per day)
treatment (Gest. week)
intervention until OGTT
(weeks)
Prob./Comp. (years) BMI (kg/m2)
endpoint of the study
Asgharian 2019 (17) L. Acid., B. Lactis Parallel Yoghurt 5 1010 22–24 4** 64/64 29.5 ± 6.2 29.2 ± 6.9 Plasma glucose
during OGTT Callaway 2019 (13) B. Lactis, L. Ramnosus Parallel Capsules >1 109 0–20 12** 207/204 31.3 ± 4.7 31.9 ± 7.5 GDM incidence
Laitinen 2009 (6) B. Lactis, L. Ramnosus Parallel Capsules 1010 0–16 NR*** 85/86 29.7 ± 4.1 NR Mother FPG,
HbA1c, insulin, HOMA, QUICKI
Lindsay 2014 (7) L. Salivarius Parallel Capsules 109 24 4 83/82 31.4 ± 5.0 32.9 ± 2.4 Change in
maternal FPG Oksene-Gafa 2019 (14) B. Lactis, L. Ramnosus 2x2 factorial Capsules >6.5 109 12–17 12** 115/115 28.8 ± 5.7 38.8 ± 6.1 Maternal GWG;
infant birthweight Pellonpera 2019 (15) B. Lactis, L. Ramnosus Parallel Capsules 1010 0–18 12.5 ± 3.1* 219/219 30.8 ± 4.7 29.5 ± 4.3 GDM incidence
Whickens 2017 (4) L. Ramnosus Parallel Capsules 6x109 14–16 13* 212/211 34.0 ± 6.0 25.5 ± 4.0 Eczema
incidence in the child at 12 months
All trials enrolled women without diabetes. All trials were placebo controlled. The assessment of incident gestational diabetes was performed at the 24-28th week by 75-gr Oral Glucose Tolerance Test, with the exception of Lindsay 2014 (7) that performed a 3-h 100 gr OGTT at the 28th week.
Age and BMI are reported as mean ± standard deviation.
CFU: colony-forming units; BMI: body mass index; GDM: gestational diabetes mellitus; OGTT: Oral Glucose Tolerance Test; FPG: fasting plasma glucose; GWG: gestational weight gain; L: Lactobacillus; Acid.: Acidophilus; B.: Bifidobacterium; Gest. Gestational; Prob/Comp: Probiotics/Comparator; NR: Not Reported.
* According to the study design, the probiotics supplementation was provided from the first study visit, throughout the pregnancy, and until 6 months postpartum **According to the study design, the probiotics supplementation was provided from enrollment until birth
*** According to the study design, the probiotics supplementation was provided from the first study visit, throughout the pregnancy, and until the end of exclusive breast-feeding
dia bet es rese ar ch a n d c li nic a l p ra ct ice 162 ( 202 0) 10 8111
5
Table 2 – Principal characteristics of the trials (all placebo-controlled) included in the analysis for other endpoints.
First author, publication year (ref)
Intervention Study design Form Dosage
(CFU/caps. per day)
Beginning of intervention (Gest. week) Duration of intervention (Weeks) # patients Prob/Comp Age (years) Prepregnancy BMI (kg/m2)
Primary endpoint of the study Included in the
analysis for FPG
Studies enrolling women without diabetes Allen 2010
(24)
L. salivarius, L. paracasei, B. Lactis,
B. Bifidum
Parallel Capsules 1.25x109 36 4 220/234 29.0 ± 5.6 NR Maternal and fetal adverse events No
Asemi 2013 (22) L. Acid,
B. BB12, S. Termop, L. bulgaricus
Parallel Yoghurt <107 Third trimester 9 37/33 24.2 ± 3.3 NR Change in maternal FPG, insulin, insulin
resistance
Yes
Asgharian 2019 (17) L. Acid., B. Lactis Parallel Yoghurt 5 1010 22–24 4* 64/64 29.5 ± 6.2 29.2 ± 6.9 Plasma glucose during OGTT Yes
Callaway 2019 (13) B. Lactis, L. Ramnosus Parallel Capsules >1 109 0–20 12* 207/204 31.3 ± 4.7 31.9 ± 7.5 GDM incidence Yes
Jamilian 2016 (9) L. Acid, L. Casei, B. Bifidus Parallel Capsules 2 109 9–12 12 30/30 28.4 ± 5.3 25.5 ± 4.1 Metabolic profile, inflammation and
oxidative stress
Yes
Laitinen 2009 (6) B. Lactis, L. Ramnosus Parallel Capsules 1010 0–16 12** 85/86 29.7 ± 4.1 NR Change in mother FPG, HbA1c, insulin,
HOMA, QUICKI
Yes
Lindsay 2014 (7) L. Salivarius Parallel Capsules 109 24 4 83/82 31.4 ± 5.0 32.9 ± 2.4 Change in maternal FPG Yes
Mantaring 2018 (23) B. Lactis, L. Ramnosus Parallel Capsules 7x108 24–28 Until 2 months
post birth
70/70 25.5 ± 5.4 20.6 ± 2.9 Incidence of diarrhea in infants No
Oksene-Gafa 2019 (14)
B. Lactis, L. Ramnosus 2x2 Capsules >6.5 109 12–17 12 115/115 28.8 ± 5.7 38.8 ± 6.1 Maternal excessive GWG; infant birthweight Yes
Pellonpera 2019 (15) B. Lactis, L. Ramnosus Parallel Capsules 1010 0–18 14* 219/219 30.8 ± 4.7 29.5 ± 4.3 GDM incidence Yes
Whickens 2017 (4) L. Ramnosus Parallel Capsules 6x109 14–16 12*** 212/211 34.0 ± 6.0 25.5 ± 4.0 Eczema incidence in the child at 12 months Yes
Studies enrolling women with gestational diabetes Badehnoosh 2018 (19) L. Acid.,
L. Casei, B. Bifidum
Parallel Capsules 2 109 24–28 6 30/30 28.8 ± 5.4 28.3 ± 3.9 Inflammatory markers Yes
Dolatkhah 2015 (5) L. Acid, B. BB12,
S. Termop, L. Bulgaricus
Parallel Capsules 4 109 24–28 8 29/27 28.1 ± 6.2 31.4 ± 3.9 Change in maternal HOMA Yes
Jafarnejad 2016 (21) VSL#3$ Parallel Capsules 112.5 109 24–28 8 41/41 32.4 ± 3.1 26.8 ± 2.7 Inflammatory and metabolic parameters Yes
Karamali 2016 (20) L. Acid., L. Casei, B. Bifidum
Parallel Capsules 2x109 24–28 6 30/30 31.8 ± 6.0 28.6 ± 4.2 Glucose homeostasis parameters Yes
Kijmanawat 2019 (16) L. Acid., B. Bifidus Parallel Capsules 109 24–28 4 30/30 32.5 ± 5.0 22.7 ± 3.7 Change in mother FPG, HbA1c, insulin,
HOMA
Yes
Lindsay 2015 (8) L. Salivarius Parallel Capsules 109 <34 4–6 74/75 33.5 ± 5.0 29.6 ± 6.7 Change in maternal FPG Yes
All trials were placebo controlled. In trials enrolling women with gestational diabetes, the diagnosis was made at the 24-28th week by 75-gr Oral Glucose Tolerance Test. Age and BMI are reported as mean ± standard deviation.
CFU: colony-forming units; BMI: body mass index; HOMA: Homeostastis Model Assessment; FPG: fasting plasma glucose; GWG: gestational weight gain; L: Lactobacillus; Acid.: Acidophilus; B.: Bifidobacterium; S.: Streptococcus; Termop.: Termophilus; Gest. Gestational; Prob/Comp: Probiotics/Comparator; NR: Not Reported.
$VSL#3 is a mixture of Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, and Lactobacillus delbrueckii subsp. Bulgaricus
* weeks of treatment, until FPG evaluation; intervention lasted until birth for all the other endpoints. **weeks of treatment, until FPG evaluation; intervention lasted until the end of breastfeeding *** weeks of treatment, until FPG evaluation; intervention lasted until 6 months post birth
6
di ab e t es re s e ar ch and c lin i c a l p ra ct ic e 16 2 ( 20 20) 1 0811 13.3.2. Infant
Seven trials reported information on macrosomia, showing no significant effect of probiotic treatment (MH-OR, 95% CI: 1.11 [0.84, 1.47], p = 0.47), as reported inFig. S8.
When considering birth weight, no effect of probiotics in comparison with placebo was detected (MD, 95%CI: 11.86 [ 70.51, 46.80] g, p = 0.69, Fig. S9), although a non-significant trend toward birth weight reduction was observed in trials enrolling women with GDM (n = 5, MD, 95%CI: 90.0 [ 180.7, 0.7] g, p = 0.050). Information on jaundice was reported in 3 trials, showing a not significant reduction with probiotics (MH-OR, 95% CI: 0.44 [0.16, 1.18], p = 0.10, Fig. S10); notably, assessment of I2 statistics suggests high heterogeneity (I2: 73%). No effect of probiotic was observed
on preterm birth (MH-OR, 95% CI: 1.23 [0.69, 2.20], p = 0.48, Fig. S11), as well as on admission in intensive care unit (MH-OR, 95% CI: 0.97 [0.75, 1.27], p = 0.83,Fig. S12). Moreover, probiotics did not affect the incidence of neonatal hypogly-caemia (MH-OR, 95% CI: (1.03 [0.72, 1.47], p = 0.88, Fig. S13) and intrauterine/perinatal death (MH-OR, 95% CI: 0.78 [0.37, 1.64], p = 0.51,Fig. S14).
4.
Discussion
This meta-analysis shows that probiotic supplementation dur-ing pregnancy does not reduce the incidence of GDM, whereas a very little (statistically but not clinically significant) reduction of fasting plasma glucose is observed in women taking probi-Fig. 2 – Risk of incident diabetes for probiotics versus control groups (MH-OR, 95% CI: Mantel-Haenzel Odds Ratio, with 95% of Confidence Intervals).
Fig. 3 – Between-group differences (probiotics versus control groups) in fasting plasma glucose (mg/dl). Results are reported for trials performed on women with and without gestational diabetes (95% CI: 95% of Confidence Intervals).
otics. This result is in line with that of a previous meta-analysis on a smaller number of trials[12]. The concurrent reduction of fasting insulinemia, and the consequent improvement of the HOMA index, suggest that this effect is attributable to an increase in insulin sensitivity, rather than to an enhancement of insulin secretion. This finding is in line with several trials conducted in pregnant women[6,15,23]and in patients with type 2 diabetes[25,26]and metabolic syndrome[27].
Despite the statistical significance of results, their clinical relevance is questionable, considering the small size of the effect. Not surprisingly, the GRADE framework provided a classification of evidence as ‘‘moderate”. In order to establish the possible clinical impact of the effect of probiotics on fast-ing glucose, women with and without GDM should be consid-ered separately. The reduction of fasting glucose is not significant in separate analyses performed on women either with or without GDM; however, sample sizes could be too small to detect differences in subgroup analyses.
In women without GDM, the main possible benefit of an intervention that improves insulin sensitivity should be the reduction of incident GDM. In the present metanalysis, despite the inclusion of some recent trials, the effect of probi-otics in this regard is not statistically significant. However, sample sizes are still very small, resulting in a limited sensi-tivity of analyses. In women with GDM, a treatment produc-ing effects on glucose metabolism is clinically useful if it determines a reduction of blood glucose enough to prevent maternal, fetal, and neonatal complications. In trials with probiotics, the observed reduction of fasting glucose in women with GDM is actually very small. Therefore, it is not surprising that those treatments fail to produce significant effects on maternal and fetal outcomes, although sample sizes could have been too small for a reliable assessment of some endpoints. On the other hand, no signal of safety issues emerged from this analysis.
Although it is uncertain exactly how probiotics might exert beneficial effects on glucose metabolism, the effect could be mediated by the gut flora[28]. Short-chain fatty acids (SCFAs) are the main product of bacterial fermentation of fiber in the gut and are significantly changed in the intestinal lumen during pregnancy [29]. It was suggested that SCFAs play an important role in the metabolism of pregnant women. Moreover, probiotics could improve insulin resistance through their anti-inflammatory effects. Probiotics decrease the levels of the inflammatory markers including tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) and increase intestinal GLP-1 levels reducing glucotoxicity and increasing increase insulin sensitivity in pregnant women[30]
In addition, some limitations of the present metanalysis should be acknowledged. The reliability of the assessment of publication bias is questionable, because of the small number of available trials. For the same reason, it is not possible to explore factors that determine heterogeneity, which is relevant for both the principal outcomes. Furthermore, probiotics used differ across trials, adding uncertainty to the interpretation of results.
In conclusion, probiotic supplementation during preg-nancy is associated with no benefits on the incidence of ges-tational diabetes but it produces a minimal improvement of fasting glucose, which appears to be determined by an
increase in insulin sensitivity. Although safe, this treatment does not show, on the basis of currently available trials, suffi-cient clinical benefits for recommending its widespread use.
5.
Role of the funding source
This research was performed with no specific funding.
Author contributions
The manuscript was drafted and revised by the authors in accordance with ICJME standards for authorship. The corre-sponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
MM, EV and MM were involved in each of the following points:
1. Design 2. Data Collection 3. Analysis
4. Writing manuscript
FF and GDP were involved in the following point: 1. Manuscript revision
EM was involved in each of the following points: 1. Design
2. Manuscript revision
All the authors approved the final version of this manuscript
Declaration of Competing Interest
All authors declare no conflicts of interest.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.org/10.1016/j.diabres.2020.108111.
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